Mutations in the GBA1 gene are the most common of the known risk factors for Parkinson disease (PD). While clinical studies argue a strong case towards a link between GBA1 mutations and the development of PD, mechanistic insights have been lacking. GBA1 encodes glucocerebrosidase (GCase), a lysosomal enzyme which hydrolyzes glucosylceramide (GluCer) into glucose and ceramide and is deficient in Gaucher disease (GD). Recent research suggests a relationship between GCase and the PD-related amyloid-forming protein, alpha-synuclein (alpha-syn); however, the specific molecular mechanisms responsible for association remain elusive. While the effects of GCase on alpha-syn homeostasis are the subject of considerable work, a role for alpha-synuclein in enzyme function has not been established. Such information could have further implications and indicate other mechanisms responsible for the increased PD risk. A growing number of studies show a correlation between GCase deficiency and increased alpha-syn levels, leading some to speculate that GluCer accumulation affects normal &#945;-syn turnover. Intriguingly, we discovered a specific physical interaction exists between alpha-syn and GCase both in solution and on the lipid membrane, resulting in efficient enzyme inhibition. It is currently unresolved whether reduced GCase activity alone leads to increased alpha-syn levels. Since only a minority of GD patients and carriers develop PD, other factors are also expected to play a role in promoting pathogenesis. Obvious molecules of interest include those that modulate GCase activity and alpha-syn-GCase interaction. To address this, we have investigated whether Sap C, a vital co-factor in vivo, can affect GCase activity inhibition by alpha-syn in vitro. Remarkably, Sap C protects GCase from alpha-syn inhibition in a concentration dependent manner. Using NMR spectroscopy, site-specific fluorescence, and Frster energy transfer probes, Sap C was observed to displace alpha-syn from GCase in solution and on lipid vesicles. Taken together with the reported inverse correlation between GCase and alpha-syn levels derived from tissue culture, animal models, and patients, Sap C could act as a modifier in the homeostasis of alpha-syn. Our results might suggest different disease implications. First, the high neuronal levels of alpha-syn could lead to greater attenuation of GCase activity in patients deficient in Sap C, and this association could potentially explain why GBA1 mutations cause neuronopathic GD in some patients, but not in others. Second, if alpha-syn-GCase interaction promotes PD pathology via activity inhibition, then Sap C could play a protective role by removing alpha-syn from GCase. In this scenario, Sap C deficiency would be a risk factor for PD. Alternatively, if interaction of alpha-syn with GCase is involved in its normal lysosomal degradation as previously hypothesized, then increased Sap C levels displacing alpha-syn could potentially be harmful. Further investigation is clearly needed to determine if and to what extent Sap C and/or the interplay between Sap C, alpha-syn, and GCase is involved in PD.